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首页> 美国卫生研究院文献>Springer Open Choice >Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease: diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and Aβ42 levels
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Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease: diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and Aβ42 levels

机译：Creutzfeldt-Jakob病中的蛋白特异性和替代性CSF生物标志物：与分子亚型相关的诊断准确性以及p-tau和Aβ42水平的神经病理学关联分析

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The differential diagnosis of Creutzfeldt-Jakob disease (CJD) from other, sometimes treatable, neurological disorders is challenging, owing to the wide phenotypic heterogeneity of the disease. Real-time quaking-induced prion conversion (RT-QuIC) is a novel ultrasensitive in vitro assay, which, at variance with surrogate neurodegenerative biomarker assays, specifically targets the pathological prion protein (PrPSc). In the studies conducted to date in CJD, cerebrospinal fluid (CSF) RT-QuIC showed good diagnostic sensitivity (82–96%) and virtually full specificity. In the present study, we investigated the diagnostic value of both prion RT-QuIC and surrogate protein markers in a large patient population with suspected CJD and then evaluated the influence on CSF findings of the CJD type, and the associated amyloid-β (Aβ) and tau neuropathology. RT-QuIC showed an overall diagnostic sensitivity of 82.1% and a specificity of 99.4%. However, sensitivity was lower in CJD types linked to abnormal prion protein (PrPSc) type 2 (VV2, MV2K and MM2C) than in typical CJD (MM1). Among surrogate proteins markers (14-3-3, total (t)-tau, and t-tau/phosphorylated (p)-tau ratio) t-tau performed best in terms of both specificity and sensitivity for all sCJD types. Sporadic CJD VV2 and MV2K types demonstrated higher CSF levels of p-tau when compared to other sCJD types and this positively correlated with the amount of tiny tau deposits in brain areas showing spongiform change. CJD patients showed moderately reduced median Aβ42 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of Aβ brain deposits. Our results: (1) support the use of both RT-QuIC and t-tau assays as first line laboratory investigations for the clinical diagnosis of CJD; (2) demonstrate a secondary tauopathy in CJD subtypes VV2 and MV2K, correlating with increased p-tau levels in the CSF and (3) provide novel insight into the issue of the accuracy of CSF p-tau and Aβ42 as markers of brain tauopathy and β-amyloidosis.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1683-0) contains supplementary material, which is available to authorized users.
机译：由于该疾病广泛的表型异质性，因此将其与其他有时可以治疗的神经系统疾病区别诊断为克雅氏病（CJD）具有挑战性。实时地震诱导的pr病毒转化（RT-QuIC）是一种新颖的超灵敏体外测定法，与替代性神经退行性生物标记物测定法不同，它特异性地靶向病理病毒蛋白（PrP Sc ）。迄今为止，在CJD中进行的研究中，脑脊液（CSF）RT-QuIC表现出良好的诊断敏感性（82–96％）和几乎完全的特异性。在本研究中，我们调查了ion病毒RT-QuIC和替代蛋白标记物在疑似CJD的大量患者人群中的诊断价值，然后评估了对CJD型CSF发现以及相关淀粉样β-（Aβ）的影响和tau神经病理学。 RT-QuIC显示总诊断灵敏度为82.1％，特异性为99.4％。但是，与异常abnormal病毒蛋白（PrP Sc ）2型（VV2，MV2K和MM2C）相关的CJD类型的敏感性低于典型CJD（MM1）。在所有sCJD类型的特异性和敏感性方面，替代蛋白质标记（14-3-3，总（t）-tau和t-tau /磷酸化的（p）-tau比）中，t-tau表现最佳。与其他sCJD类型相比，偶发的CJD VV2和MV2K类型显示出较高的p-tau CSF水平，这与脑部显示海绵状变化的微小tau沉积物数量呈正相关。 CJD患者显示中度Aβ42CSF水平降低，其中38％的患者在没有Aβ脑沉积的情况下蛋白质水平显着降低。我们的结果：（1）支持将RT-QuIC和t-tau检测法用作CJD临床诊断的一线实验室研究； （2）证明CJD亚型VV2和MV2K中存在继发性tauopathy，与CSF中p-tau水平升高相关；（3）提供了对CSF p-tau和Aβ42准确度问题的新见解，ASF42是脑tauopathy和β-淀粉样变性病。电子补充材料本文的在线版本（doi：10.1007 / s00401-017-1683-0）包含补充材料，可供授权用户使用。

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